SENCAR mice are markedly more susceptible to skin carcinogenesis than other mouse strains. Susceptibility, a property of the skin itself, is not due to differences in carcinogen metabolism. Cultures of both basal and differentiating epidermal cells of new born SENCAR and BALB/c (a resistant strain) mice responded similarly to modulation of epidermal growth factor (EGF) binding by treatment with the tumor promoter TPA or with retinoic acid, but when basal cells were induced to differentiate, SENCAR lost EGF binding ability to a greater extent. TPA treatment of the basal cells caused a rapid and profound decrease in EGF binding while retinoic acid treatment resulted in increased binding and was partially protective against TPA effect. Differentiating cells responded much less TPA, and retinoic acid was suppressive rather than stimulatory. Differentiating cells, in contrast to basal cells, bind but do not metabolize EGF. EGF stimulated epidermal basal cell growth in the absence of other cell types or conditioned media but only if cell proliferation was already occurring. TPA and retinoic acid treatment induced transglutaminase activity in epidermal cells of both mouse strains similarly by a mechanism involving a protease. Treatment of mouse skin of either strain in vivo or of primary epidermal cells in vitro with tumor promoters led to increased numbers of Langerhans cells. Methods were devised to enhance survival and enrich cultures for this cell type. Culture conditions for adult mouse epidermal cells have been developed and studies have begun to develop and characterize carcinogen-initiated cells selected for resistance to calcium-induced terminal differentiation.